N-(2,3-Dihydroxypropoxy)-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide is a MEK inhibitor described in WO 2002006213 A2 (Barrett et al.) and EP 1262176 A1 (Baragi et al.), the entire disclosure of which are incorporated herein by reference. MEK inhibitors are compounds which inhibit one or more of the family of mammalian enzymes known as MAP kinase kinases, which phosphorylate the MAP kinase subfamily of enzymes (mitogen-associated protein kinase enzymes) referred to as MAP kinases or ERKs (extracellular signal-regulating enzymes such as ERK1 and ERK 2). These enzymes regulate phosphorylation of other enzymes and proteins within the mammalian body. MEK 1 and MEK 2, as well as ERK1 and ERK 2, are dual specificity kinases that are present in all cell types and play a critical role in the regulation of cell proliferation and differentiation in response to mitogens and a wide variety of growth factors and cytokines. Upon activation, these enzymes control a cascade that can phosphorylate a large number of substrates, including transcription factors, the EGF receptor, phospholipase A2, tyrosine hydroxylase, and cytoskeletal proteins. One selective MEK inhibitor has been shown to be useful to treat a number of proliferative disorders, including psoriasis, restenosis, and cancer, as described in U.S. Pat. No. 5,525,625, incorporated herein by reference. A whole series of MEK inhibitors have been described as useful to prevent and treat septic shock, see WO 98/37881, incorporated herein by reference.
Crystalline polymorphs are different crystalline forms of the same compound. The term polymorph may or may not include other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound. Different crystalline polymorphs have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters which directly influences its physical properties such the X-ray diffraction characteristics of crystals or powders. A different polymorph, for example, will in general diffract at a different set of angles and will give different values for the intensities. Therefore X-ray powder diffraction can be used to identify different polymorphs, or a solid form that comprises more than one polymorph, in a reproducible and reliable way (S. Byrn et al, Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations, Pharmaceutical research, Vol. 12, No. 7, p. 945–954, 1995; J. K. Haleblian and W. McCrone, Pharmacetical Applications of Polymorphism, Journal of Pharmaceutical Sciences, Vol. 58, No. 8, p. 911–929,1969).
Crystalline polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.
US 2004/0054172, the entire disclosure of which is incorporated herein by reference, provides crystalline Form I and Form II of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (referred to as “Form I” and “Form II”, respectively) or hydrates thereof, crystalline Form I and Form II of N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide or hydrates thereof, and crystalline Form I and Form II of N-[(S)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide or hydrates thereof, which are useful as pharmaceutical agents, methods for their production and isolation, pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and pharmaceutical methods of treatment. The disclosed crystalline compounds of US 2004/0054172 are useful as inhibitors of MEK.